Diabetic Peripheral Neuropathy in the Macrocirculatory and Microcirculatory Chronic Limb-Threatening Ischemia Puzzle: Does It Act as an Additional Factor for Vascular Damage? - 2026
Diabetic Peripheral Neuropathy in the Macrocirculatory and Microcirculatory Chronic Limb-Threatening Ischemia Puzzle: Does It Act as an Additional Factor for Vascular Damage?
ALEXANDRESCU, Vlad-Adrian; van den Berg, Jos; Kerzmann, Arnaudet al.
2026 • In Journal of Critical Limb Ischemia, 6 (3), p. 107-E118
ALEXANDRESCU, Vlad-Adrian ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chirurgie cardio-vasculaire et thoracique
van den Berg, Jos; Centro Vascolare Ticino, Ospedale Regionale di Lugano, Switzerland
Kerzmann, Arnaud ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chirurgie cardio-vasculaire et thoracique
BOESMANS, Evelyne ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chirurgie cardio-vasculaire et thoracique
Tchana-Sato, Vincent ; Université de Liège - ULiège > Département des sciences cliniques > Chirurgie cardio-vasculaire
Language :
English
Title :
Diabetic Peripheral Neuropathy in the Macrocirculatory and Microcirculatory Chronic Limb-Threatening Ischemia Puzzle: Does It Act as an Additional Factor for Vascular Damage?
1. Saeedi P, Petersohn I, Salpea P, et al; IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. doi:10.1016/j.diabres.2019.107843
2. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154. doi:10.2337/dc16-2042
3. Sun J, Wang Y, Zhang X, Zhu S, He H. Prevalence of peripheral neuropathy in pa-tients with diabetes: a systematic review and meta-analysis. Prim Care Diabetes. 2020;14(5): 435-444. doi:10.1016/j.pcd.2019.12.005
4. Mills JL Sr, Conte MS, Armstrong DG, et al; Society for Vascular Surgery Lower Extremity Guidelines Committee. The Society for Vascular Surgery lower extremity threatened limb classification system: risk stratification based on wound, isch-emia, and foot infection (WIfI). J Vasc Surg. 2014;59(1):220-234.e1-2. doi:10.1016/j. jvs.2013.08.003
5. Nukada H. Ischemia and diabetic neuropathy. Handb Clin Neurol. 2014;126:469-4487. doi:10.1016/B978-0-444-53480-4.00023-0
6. Lewi MJ, ed. The Textbook of Chiropody. The School of Chiropody of New York; 1914.
7. Sanders LJ, Robbins JM, Edmonds ME. History of the team approach to amputa-tion prevention: pioneers and milestones. J Vasc Surg. 2010; 52(3 Suppl):3S-16S. doi:10.1016/j.jvs.2010.06.002
8. Edmonds ME, Morrison N, Laws JW, Watkins PJ. Medial arterial calcification and diabetic neuropathy. Br Med J (Clin Res Ed). 1982;284(6320):928-930. doi:10.1136/ bmj.284.6320.928
9. Gilbey SG, Walters H, Edmonds ME, et al. Vascular calcification, autonomic neu-ropathy, and peripheral blood flow in patients with diabetic nephropathy. Diabet Med. 1989;6(1):37-42. doi:10.1111/j.1464-5491.1989.tb01136.x
10. Alexandrescu VA, Van Overmeire L, Makrygiannis G, et al. Clinical implications of diabetic peripheral neuropathy in primary infrapopliteal angioplasty ap-proach for neuro-ischemic foot wounds. J Endovasc Ther. 2023;30(6):920-930. doi:10.1177/15266028221106312
11. Lanzer P, Boehm M, Sorribas V, et al. Medial vascular calcification revisited: review and perspectives. Eur Heart J. 2014;35(23):1515-1525. doi:10.1093/eurheartj/ehu163
12. Conte MS, Bradbury AW, Kolh P, et al; GVG Writing Group. Global vascular guide-lines on the management of chronic limb-threatening ischemia. J Vasc Surg. 2019;69(6S):3S-125S.e40. doi:10.1016/j.jvs.2019.02.016.
13. Powers AC. Type 1 diabetes mellitus: much progress, many opportunities. J Clin Invest. 2021;131(8):e142242. doi:10.1172/JCI142242
14. Chang MC, Yang S. Diabetic peripheral neuropathy essentials: a narrative review. Ann Paliat Med. 2023;12(2):390-398. doi:10.21037/apm-22-693
15. Cheng Y, Chen Y, Li K, et al. How inflammation dictates diabetic peripheral neurop-athy: an enlightening review. CNS Neurosci Ther. 2024;30(4):e14477. Doi:10.1111/ cns.14477
16. Yang P, Feng J, Peng Q, Liu X, Fan Zhongcai. Advanced glycation end products: potential mechanism and therapeutic target in cardiovascular complications under diabetes. Oxid Med Cell Longev. 2019;2019:9570616. doi:10.1155/2019/9570616
17. Alexandrescu VA, Kerzmann A, Boesmans E, Tchana-Sato V. Microangiopathic disease in the diabetic neuro-ischemic feet: a threatening, often understated contributor, for tissue and limb loss. Medical Research Archives. 2025;13(7). doi:10.18103/mra. v13i7.6730
18. Iqbal Z, Bashir B, Ferdousi M, et al. Lipids and peripheral neuropathy. Curr Opin Lipidol. 2021;32(4):249-257. doi:10.1097/MOL.0000000000000770.
19. Wu S, Cao X, He R, Xiong K. Detrimental impact of hyperlipidemia on the peripheral nervous system: a novel target of medical epidemiological and fundamental research study. Neural Regen Res. 2012;7(5):392-399. doi:10.3969/j.issn.1673-5374.2012.05.011
20. Ahmadi SAY, Shirzadegan R, Mousavi N, Farokhi E, Soleimaninejad M, Jafarzadeh M. Designing a logistic regression model for a dataset to predict diabetic foot ulcer in diabetic patients: high-density lipoprotein (HDL) cholesterol was the negative predictor. J Diabetes Res. 2021;2021:5521493. doi:10.1155/2021/5521493
21. Yip J, Mattock MB, Morocutti A, Sethi M, Trevisan R, Viberti G. Insulin resis-tance in insulin-dependent diabetic patients with microalbuminuria. Lancet. 1993;342(8876):883-887. doi:10.1016/0140-6736(93)91943-g
22. Alam U, Petropoulos IN, Ponirakis G, et al. Vitamin D deficiency is associated with painful diabetic neuropathy. Diabetes Metab Res Rev. 2021;37(1):e3361. doi:10.1002/ dmrr.3361
23. Jin HY, Park TS. Role of inflammatory biomarkers in diabetic peripheral neuropathy. J Diabetes Investig. 2018;9(5):1016-1018. doi:10.1111/jdi.12794
24. Horton WB, Barrett EJ. Microvascular dysfunction in diabetes mellitus and car-diometabolic disease. Endocr Rev. 2020;42(1):29-55. doi:10.1210/endrev/bnaa025
25. Alexandrescu VA, Kerzmann A, Tchana-Sato V. Diabetic neuro-ischaemic foot syndrome and the key underlying interactions between chronic arterial disease and peripheral neuropathy. Medical Research Archives. 2025;13(2). doi:10.18103/ mra.v13i2.6364
26. Taylor GI, Gianoutsos MP, Morris SF. The neurovascular territories of the skin and muscles: anatomic study and clinical implications. Plast Reconstr Surg. 1994;94(1):1-36. doi:10.1097/00006534-199407000-00001
27. Mauricio D, Gratacòs M, Franch-Nadal J. Diabetic microvascular disease in non-clas-sical beds: the hidden impact beyond the retina, the kidney, and the peripheral nerves. Cardiovasc Diabetol. 2023;22(1):314. doi:10.1186/s12933-023-02056-3
28. Mansour A, Mousa M, Abdelmannan D, Tay G, Hassoun A, Alsafar H. Microvas-cular and macrovascular complications of type 2 diabetes mellitus: exome wide association analyses. Front Endocrinol (Lausanne). 2023;14:1143067. doi:10.3389/ fendo.2023.1143067
29. Weber S, Ziegler A. Axonal neuropathy in chronic peripheral arterial occlusive disease. Muscle Nerve. 2002; 26(4):471-476. doi:10.1002/mus.10235
30. Alexandrescu VA, Neville RF, Kerzmann A, et al. Applicability of intentional topo-graphic revascularization following the angiosome model in patients with chronic limb-threatening ischemia: from theory, to current clinical challenges. Clin Surg. 2024; 9:3701. doi:10.25107/cis-v9-id3701
31. O'Neal LW. Surgical pathology of the foot and clinicopathologic correlations. The end-artery occlusive disease conception. In: Bowker JH, Pfeifer MA. Levin and O'Neal's Diabetic Foot. 7th ed. 2007;Mosby Elsevier;367-401.
32. Iida O, Takahara M, Ohura N, et al; WARRIORS Investigators. Editor's Choice -Impact of infrapopliteal revascularisation establishing in line flow to the wound in patients with chronic limb threatening ischaemia. Eur J Vasc Endovasc Surg. 2024;68(5):631-638. doi:10.1016/j.ejvs.2024.07.024
33. Patrone L, Pasqui E, Conte MS, et al. The "woundosome" concept and its impact on procedural outcomes in patients with chronic limb-threatening ischemia. J Endovasc Ther. 2025;32(6):1765-1776. doi:10.1177/15266028241231745
34. Mustapha JA, Diaz-Sandoval LJ, Saab F. Infrapopliteal calcification patterns in critical limb ischemia: diagnostic, pathologic and therapeutic implications in the search for the endovascular holy grail. J Cardiovasc Surg (Torino). 2017;58(3):383-401. doi:10.23736/S0021-9509.17.09878-0
35. Teso D, Sommerset J, Dally M, Feliciano B, Vea Y, Jones RK. Pedal acceleration time (PAT): a novel predictor of limb salvage. Ann Vasc Surg. 2021;75: 189-193. doi:10.1016/j.avsg.2021.02.038
36. Malik RA. Pathology of human diabetic neuropathy. Handb Clin Neurol. 2014;126:249-259. doi:10.1016/B978-0-444-53480-4.00016-3
37. Rosenberg DC, Blechschmidt V, Timmerman H, Wolff A, Treede R. Challenges of neuropathic pain: focus on diabetic neuropathy. J Neural Transm (Vienna). 2020;127(4):589-624. doi:10.1007/s00702-020-02145-7
38. Schraepen C, van der Laan L, Smet N, Meulenbroek A, Fourneau I. Chronic limb-threat-ening Ischemia does not enclose a homogeneous population: time for a more detailed classification. Int J Angiol. 2023;33(1):8-14. doi:10.1055/s-0043-1777414
39. Young MJ, Boulton AJ, Macleod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993;36(2):150-154. doi:10.1007/BF00400697
40. Lanzer P, Ferraresi R. Medial sclerosis-epidemiology and clinical significance. Dtsch Arztebl Int. 2023;120(21):365-372. doi:10.3238/arztebl.m2023.0066
41. Alexandrescu VA, Deloose KR, Kerzmann A. From diabetic foot microvascular disease to medial arterial sclerosis and calcification in chronic limb-threatening ischemia: a potentially unified pathogenic and prognostic entity for tissue and limb loss. Clin Cardiol Cardiovasc Interv. 2026;9(2):1-10. doi:10.31579/2641-0419/547
42. Hicks CW, Selvin E. Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. Curr Diab Rep. 2019;19(10):86. doi:10.1007/s11892-019-1212-8
43. Pop-Busui R, Lu J, Lopes N, Jones TLZ, BARI 2D Investigators. Prevalence of diabetic peripheral neuropathy and relation to glycemic control therapies at baseline in the BARI 2D cohort. J Peripher Nerv Syst. 2009;14(1):1-13. doi:10.1111/j.1529-8027.2009.00200.x
44. Behroozian A, Beckman JA. Microvascular disease increases amputation in patients with peripheral artery disease. Arterioscler Thromb Vasc Biol. 2020;40(3):534-540. doi:10.1161/ATVBAHA.119.312859
45. van den Berg JC. Angiosome perfusion of the foot: an old theory or a new issue? Semin Vasc Surg. 2018;31(2-4):56-65. doi:10.1053/j.semvascsurg.2018.12.002
46. Sharma S, Schaper N, Rayman G. Microangiopathy: is it relevant to wound healing in diabetic foot disease? Diabetes Metab Res Rev; 2020;36 Suppl 1:e3244. doi:10.1002/ dmrr.3244
47. Petropoulos IN, Ponirakis G, Khan A, Almuhannadi H, Gad H, Malik RA. Diagnosing diabetic neuropathy: something old, something new. Diabetes Metab J. 2018;42(4):255-269. doi:10.4093/dmj.2018.0056
48. Yorec M, Malik RA, Calcutt NA, Vinik A, Yagihashi S. Diabetic neuropathy: new insights to early diagnosis and treatments. J Diabetes Res. 2018:5378439. doi:10.1155/2018/5378439
49. Hingorani A, LaMuraglia GM, Henke P, et al. The management of the diabetic foot: a clinical practice guideline by the Society for Vascular Surgery in collaboration with the American Podiatric Medical Association and the Society for Vascular Medicine. J Vasc Surg. 2016;63(2 Suppl):3S-21S. doi:10.1016/j.jvs.2015.10.003
50. Tesfaye S, Boulton AJM, Dyck PJ, et al; Toronto Diabetic Neuropathy Expert Group. Diabetes neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285-2293. doi:10.2337/ dc101303
51. Scholz J, Finnerup NB, Attal N, et al; Classification Committee of the Neuropathic Pain Special Interest Group (NeuPSIG). The IASP classification of chronic pain for ICD-11: chronic neuropathic pain. Pain. 2019;160(1):53-59. doi:10.1097/j. pain.0000000000001365
52. Dyck PJ, Albers JW, Andersen H, et al; Toronto Expert Panel on Diabetic Neuropathy. Diabetic polyneuropathies: update on research definition, diagnostic criteria and estimation of severity. Diabetes Metab Res Rev. 2011;27(7):620-628. doi:10.1002/ dmrr.1226
53. England JD, Gronseth, GS, Franklin G, et al; American Academy of Neurology. Practice parameter: evaluation of distal symmetric polyneuropathy: role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review) [RETIRED]. Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Reha-bilitation. Neurology. 2009;72(2):177-184. doi:10.1212/01.wnl.0000336345.70511.0f
54. Dyck PJ, Overland CJ, Low PA, et al. Signs and symptoms versus nerve conduction studies to diagnose diabetic sensorimotor polyneuropathy: Cl vs. NPhys trial. Muscle Nerve. 2010;42(2):157-164. doi:10.1002/ mus.21661
55. Petropoulos IN, Ponirakis G, Ferdousi M, et al. Corneal confocal microscopy: a biomarker for diabetic peripheral neuropathy. Clin Ther. 2021;43(9):1457-1475. doi:10.1016/j.clinthera.2021.04.003
56. Bäckryd E, Themistocleous A, Larsson A, et al. Eleven neurology-related proteins measured in serum are positively correlated to the severity of diabetic neuropathy. Sci Rep. 2024;14(1):17068. doi:10.1038/s41598-024-66471-6
57. Li M, Liang H, Chiang C, Wu T. Pulsatility-index adjusted doppler flow measure-ment of pedal arteries in peripheral artery disease patients. J Chin Med Assoc. 2023;86(1):98-104. doi:10.1097/JCMA.0000000000000843
58. Kim TI, Guzman RJ. Medial artery calcification in peripheral arterial disease. Front Cardiovasc Med. 2023;10:1093355. doi:10.3389/fcvm.2023.1093355
59. Chen L, Chen D, Gong H, et al. Pedal medial arterial calcification in diabetic foot ulcers: a significant risk factor of amputation and mortality. J Diabetes. 2024;16(4):e13527. doi:10.1111/1753-0407.13527
60. POSTER/ABSTRACT Kerzmann A, Valkenborgh C, Alexandrescu VA, et al. Calcium score for chronic limb-threatening ischemia: P-111. ESVS 39th Annual meeting in Istanbul, Türkiye, September 2025. Eur J Vasc Endovasc Surg; 2025. Doi: 10.1016/j. ejvs.2025.09.037.
61. Utsunomiya M, Nakamura M, Nagashima Y, Sugi K. Predictive value of skin perfusion pressure after endovascular therapy for wound healing in critical limb ischemia. J Endovasc Ther. 2014;21(5):662-670. doi:10.1583/14-4675MR.1
62. Guven G, Dijkstra A, Kuijper TM, et al. Comparison of laser speckle contrast imaging with laser Doppler perfusion imaging for tissue perfusion measurement. Microcirculation. 2023;30(1):e12795. doi:10.1111/micc.12795
63. Boezeman RPE, Becx BP, van den Heuvel DAF, Ünlü Ç, Vos JA, de Vries JPPM. Monitoring of foot oxygenation with near-infrared spectroscopy in patients with critical limb ischemia undergoing percutaneous transluminal angioplasty: a pilot study. Eur J Vasc Endovasc Surg. 2016;52(5):650-656. doi:10.1016/j.ejvs.2016.07.020
64. Chiang N, Jain JK, Sleigh J, Vasudevan T. Evaluation of hyperspectral imaging tech-nology in patients with peripheral vascular disease. J Vasc Surg. 2017;66(4):1192-1201. doi:10.1016/j.jvs.2017.02.047
65. Neubauer-Geryk J, Wielicka M, Hoffmann M, Myśliwiec M, Bieniaszewski L. The impact of disease duration on microcirculatory dysfunction in young patients with uncomplicated type 1 diabetes. Biomedicines. 2024;12(5):1020. doi:10.3390/ biomedicines12051020
66. Jett S, Thompson MR, Awasthi S, et al. Stratification of microvascular severity in the foot using spatial frequency domain imaging. J Diabetes Sci Technol. 2023;17(1):25-34. doi:10.1177/19322968211024666
67. Stacy MR, Zhou W, Sinusas AJ. Radiotracer imaging of peripheral vascular disease. J Nucl Med Technol. 2015;43(3):185-192. doi:10.2967/jnumed.112.115105
68. Diehm N. Commentary: intra-arterial subtraction angiography: what you see is not al-ways what you get. J Endovasc Ther. 2015;22(2):252-253. doi:10.1177/1526602815573231
69. Piercy C, Adam J, Harrison JN, Heiss C, Campagnolo P, Creagh-Brown B. Endo-vascular endothelial cell biopsy -a systematic review. Vasa. 2025;54(5):305-313. doi:10.1024/0301-1526/a001207
70. Baku T, Kotatsu B, Sayaka H, Hiroyuki T, Hideaki H. Observation and density estimation of a large number of skin capillaries using wide-field portable video capillaroscopy and semantic segmentation. J Biomed Opt. 2023; 28(10):106003. doi:10.1117/1.JBO.28.10.106003
71. Venermo M, Settembre N, Albäck A, et al. Pilot assessment of the repeatability of indocyanine green fluorescence imaging and correlation with traditional foot perfusion assessments. Eur J Vasc Endovasc Surg. 2016;52(4):527-533. doi:10.1016/j. ejvs.2016.06.018
72. Pantoja JL, Ali F, Baril DT, et al. Arterial spin labeling magnetic resonance imag-ing quantifies tissue perfusion around foot ulcers. J Vasc Surg Cases Innov Tech. 2022;8(4):817-824. doi:10.1016/j.jvscit.2022.09.015
73. Hunter L, Wiley A, Mckinney G, et al. Neuropathy screening for patients with peripheral vascular disease helps to identify those at an increased risk of ampu-tation, revascularization, and death. Ann Vasc Surg. 2024;100:60-66. doi:10.1016/j. avsg.2023.10.021
74. Akbari CM, Gibbons GW, Habershaw GM, LoGerfo FW, Veves A. The effect of arterial reconstruction on the natural history of diabetic neuropathy. Arch Surg. 1997;132(2):148-152. doi:10.1001/archsurg.1997.01430260046008
75. Young MJ, Veves A, Smith JV, Walker MG, Boulton AJ. Restoring lower limb blood flow improves conduction velocity in diabetic patients. Diabetologia.1995;38(9):1051-1054. doi:10.1007/BF00402174
76. Veves A, Donaghue VM, Sarnow MR, Giurini JM, Campbell DR, LoGerfo FW. The impact of reversal of hypoxia by revascularization on the peripheral nerve function of diabetic patients. Diabetologia 1996;39(3):344-348. doi:10.1007/BF00418351
77. Jujo K, Saito K, Ishida I, et al. Pilot cohort study assessing the efficacy of endo-vascular revascularization in the restoration of peripheral sensory disturbance in patients with critical limb ischemia. Circ J. 2017;81(12):1919-1926. doi:10.1253/circj. CJ-17-0405
78. Chaudhry V, Russel J, Belzberg A. Decompressive surgery of lower limbs for symmetrical diabetic peripheral neuropathy. Cochrane Database Syst Rev. 2008;2008(3):CD006152. doi:10.1002/14651858.CD006152.pub2